This application entitled Genetic/Epigenetic Susceptibility to Superfund Chemicals utilizes the disciplines of biomedicine, molecular biology, ecology, and engineering to assess the potential hazardous impact of toxic metals on humans and upon aquatic ecosystems. An underlying theme involves factors responsible for differences in genetic susceptibility of human responses to carcinogenic and toxic metals. The ecology and engineering projects will study how to reduce human exposure to these same Superfund toxic metals. The focus of the research for most project is on arsenic, chromium, and nickel and their interactions with toxic organics, such as PAH's. There are 4 biomedical projects: 1) Epigenetic Effects on Individual Susceptibility to Heavy Metal and Polycyclic Aromatic Hydrocarbon-induced DNA damage (E. Tang); 2) Detection of Cr-DNA Adducts in Human Cells (M. Costa); 3) Metal-induced Inflammatory Factors, Oxidative Stress, and Suppression of Their Effects (K. Frenkel); 4) Identification and Genetic Analysis of the Human Arsenic Efflux Pump (T. Rossman). There are 3 non-biomedical projects: 1) Mechanisms of Resistance of Aquatic Vertebrate Populations to Mixtures of Aromatic Hydrocarbon and Metal Contaminants (I. Wirgin); 2) Microbial Biogeochemical Cycling of Arsenic and of Chromium Coupled to the Biodegradation of Aromatic Contaminant Compounds (L. Young); 3) Water-Sediment Model and Criteria for Arsenic and Chrome (D.Di Toro). There is one Molecular Biology Research Support Core which supports the biomedical projects by providing expertise in utilizing the UvrABC excision method in combination with ligation-medicated PCR to map sites of metal and polycyclic aromatic hydrocarbon-induced DNA adducts. The Molecular Biology Core also supports the Affymetrix GeneChip technology and other molecular biology instruments. This program project is directed by an Administrative Core which will be responsible for planning and coordination. The Administrative Core supports a unique Government Liaison unit which reaches out to local EPA Region 2 scientific personnel. With the involvement of the EPA, Outreach specialist, molecular biologists, biomedical scientists, and engineers, we have created a truly multi-disciplinary program.